Florbetapir: Making AD A Costlier Affair

in Research Blogging by

ResearchBlogging.orgThe FDA has conditionally approved the novel contrast agent, Florbetapir, to help in the diagnosis of amyloid beta plaque build up in the brains of Alzheimer’s (or, for that purpose, any damn dementia) patients.

Now there are several reasons why I am not over the moon with this, but I will come to them later. First let me introduce you to two papers which have been very popular in toting this new diagnostic tool.

This older paper  (A) in the Journal of Nuclear Medicine comes first to mind.

In the run up to the diagnosis of Amyloid Beta peptide build up, the 11C-labeled PET tracer[N-methyl-]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (6-OH-BTA), also known as Pittsburgh compound B or PIB has long been the gold standard. However, its really short half life, about 20 minutes, is a major impediment in using it for diagnostic radiology. A radioligand with faster kinetics and longer half life was desired to make radiologic diagnosis feasible. This study in the JNM worked on the compund wait for it: (E)-4-(2-(6-(2-(2-(2-18F-fluoroethoxy)ethoxy)ethoxy)pyridin-3-yl)vinyl)-N-methyl benzenamine (18F-AV-45 or florbetapir F 18) [how’s that for a mouthful, eh?] which had a half life of 110 minutes and concluded that (bracketed texts are insertions by me):

18F-AV-45 [florbetapir] was shown in this first study in humans to be well tolerated, with no serious adverse events. The cortical target regions in patients with AD [Alzheimer’s Disease] had higher uptake of 18F-AV-45 over time than did regions in subjects who were cognitively healthy. The greatest increase in uptake occurred in the precuneus and temporal cortex of AD patients, compared with HCs [healthy controls]. Scans 50–60 min after injection produced reliable imaging results. 18F-AV-45—given its relatively long radioactive half-life, relatively rapid kinetics (requiring a short postdose waiting period and short imaging durations), and relatively long, stable plateau (providing flexibility in timing of the image)—may be a robust imaging tool and potentially well suited as a biomarker for AD in large multicenter treatment and natural history trials (e.g., Alzheimer’s Disease Neuroimaging Initiative) and for imaging in community settings.

All said and done, this was a very small study with a study group of 16 Alzheimer’s patients (Mini-Mental State Examination score, 19.3 ± 3.1; mean age ± SD, 75.8 ± 9.2 y) and a control group of 16 cognitively healthy individuals (Mini-Mental State Examination score, 29.8 ± 0.45; mean age ± SD, 72.5 ± 11.6 y). The sample size was small. This was intended to be more of a proof of concept study than anything else. Also, there was no post mortem examination to verify the radiologic findings. Overall, it was intended to establish whether this agent caused any harm or not, whether it was any good in helping amyloid beta plaques or not, and in both these counts, it was successful.

It was followed by the more recent publication in the JAMA (B).

This study was more stringent. Although the study group was still pretty small (35: 29, in effect, because 6 were used to establish the protocol of the study), it was still a well designed study in that these were terminal patients and the radiologic findings were compared with immunohistochemistry and silver stain measures of brain β-amyloid after their death used as the reference standard. In order to appreciate the occurrence of false positives, the test was run on 74 healthy individuals, between 18 and 50 years of age, presumed (???) to be free from beta amyloid plaques. It was all very tight and together! The main outcome measure was to compare the PET imaging findings with those of the post mortem findings in the 35 patients with AD. The numbers are quite pretty. Take a look:

Results Florbetapir-PET imaging was performed a mean of 99 days (range, 1-377 days) before death for the 29 individuals in the primary analysis cohort. Fifteen of the 29 individuals (51.7%) met pathological criteria for Alzheimer disease. Both visual interpretation of the florbetapir-PET images and mean quantitative estimates of cortical uptake were correlated with presence and quantity of β-amyloid pathology at autopsy as measured by immunohistochemistry (Bonferroni ρ, 0.78 [95% confidence interval, 0.58-0.89]; P <.001]) and silver stain neuritic plaque score (Bonferroni ρ, 0.71 [95% confidence interval, 0.47-0.86]; P <.001). Florbetapir-PET images and postmortem results rated as positive or negative for β-amyloid agreed in 96% of the 29 individuals in the primary analysis cohort. The florbetapir-PET image was rated as amyloid negative in the 74 younger individuals in the nonautopsy cohort.

Little to criticize here, actually. Beautiful numbers. Beautiful design. Everything is spic and span except with a financial conflict with some of the authors who either owned stocks or were employed by or were paid consultants of Avid Radiopharmaceuticals which may have had some stake in the positive outcomes of the study. Another small point of concern was the fact that the imaging reports were made by three radiologists in consultation, which would be pretty difficult to achieve in the real clinical world. As such, the FDA has laid down a condition that if this radioligand is to be marketed for diagnostic purposes, then the pharmaceuticals have to sponsor training sessions for radiologists in reading these scans and also conduct a trial on how effective the results were. This was indeed a good step, because considering the fact that there can be a large reader to reader variation, this would pave the way for a more uniform method of diagnosis.

of 18F-AV-45): 77-y-old woman with mild AD with MMSE of 24 (top) and 82-y-old cognitively healthy man with MMSE of 30 (bottom). Experimental conditions and imaging and computational parameters were identical for the 2 subjects. Counts are shown as ratio to average of gray matter in cerebellum for each subject (SUVR). “]Finally, to come to the point on why I consider this to be pretty much an exercise in escalation of costs at this point:


  1. The role of beta amyloid in the pathogenesis of Alzheimer’s disease is still largely debated. (1) Indeed, until the etiologic factors of AD are better understood, beta amyloid remains, for the most part, a clinical marker of AD.
  2. There is some evidence (2) that the deposition of beta amyloid maybe a precursor to AD, but as of now, there are no disease modifying agents or well defined preventive measures in place which have been shown to reverse the effects of the accumulation amyloid.
  3. Transgenic mouse models have shown that immunologic treatment directed against beta amyloid deposition are successful in reversing cognitive deficits (3) but how far these results are applicable to human beings is a major question. Safe methods of making this model work in man is a burning question right now.
  4. With no specific treatments or with rather weak disease modifying agents in our arsenal at present, the early diagnosis of AD is going to do the patients no good. And although this study is well designed to screen for false positives, until and unless it is administered to the community and broader epidemiological studies are conducted, it would be difficult to understand what the rates actually are.
  5. What is definitely going to happen is that more and more early diagnoses of AD will happen, and the disease burden will increase. While this will mean a lot of money for Neurologists, Radiologists and Big Pharma, it will essentially be of no benefit to the patients.
  6. With more cases of AD being diagnosed, and without any effective agents to treat the disease at present, it will be interesting to see how the focus shifts in the coming months in the AD related fields of clinical research. Now that the FDA has approved the radioligand Florbetapir as a diagnostic tool (pending training of radiologists), the interest of Big Pharma should shift towards finding the “cure” to this disease.

I  believe this may be the harbinger of interesting times for data bugs like me. It will be interesting to see how things shape up with more AD diagnoses being made using these technologies but without any effective cure in place. It will be intriguing to see what it means to cost-benefit analyses, and how it impacts a health economy already brought down to its knees by an economic downturn.

But yes, all medical research which contributes new intelligence to the collective human wisdom is welcome. I believe that this will have a great impact once we discover how to stop the progression of AD or how to treat AD. That day we shall be able to diagnose it early and treat it early: an ideal public health approach!

Papers in Focus:

A. Wong, D., Rosenberg, P., Zhou, Y., Kumar, A., Raymont, V., Ravert, H., Dannals, R., Nandi, A., Brasic, J., Ye, W., Hilton, J., Lyketsos, C., Kung, H., Joshi, A., Skovronsky, D., & Pontecorvo, M. (2010). In Vivo Imaging of Amyloid Deposition in Alzheimer Disease Using the Radioligand 18F-AV-45 (Flobetapir F 18) Journal of Nuclear Medicine, 51 (6), 913-920 DOI: 10.2967/jnumed.109.069088

B. Clark, C., Schneider, J., Bedell, B., Beach, T., Bilker, W., Mintun, M., Pontecorvo, M., Hefti, F., Carpenter, A., Flitter, M., Krautkramer, M., Kung, H., Coleman, R., Doraiswamy, P., Fleisher, A., Sabbagh, M., Sadowsky, C., Reiman, P., Zehntner, S., Skovronsky, D., & , . (2011). Use of Florbetapir-PET for Imaging  -Amyloid Pathology JAMA: The Journal of the American Medical Association, 305 (3), 275-283 DOI: 10.1001/jama.2010.2008


1. Selkoe DJ. Defining molecular targets to prevent Alzheimer disease. Arch Neurol. 2005;62:192–195.[Free Full Text]

2. Pike KE, Savage G, Villemagne VL, et al. β-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease. Brain.2007;130:2837–2844.[Abstract/Free Full Text]

3. Hock C, Konietzko U, Streffer JR, et al. Antibodies against β-amyloid slow cognitive decline in Alzheimer’s disease. Neuron. 2003;38:547–554.[CrossRef][Medline]

Skeptic Oslerphile, Scientist at the Indian Council of Medical Research, National Institute of Cholera and Enteric Diseases. Interests include: Emerging Infections, Public Health, Antimicrobial Resistance, One Health and Zoonoses, Diarrheal Diseases, Medical Education, Medical History, Open Access, Healthcare Social Media and Health2.0. Opinions are my own!


Leave a Reply

Latest from Research Blogging

Go to Top